The present invention relates to a process for preparing certain 13-hydroxy-5-ketomilbemycin derivatives, which are useful as intermediates in the preparation of therapeutically useful milbemycin derivatives, and provides certain novel 13-substituted-5-ketomilbemycin derivatives which can be involved in that preparation.
A series of 13-hydroxy-5-ketomilbemycin derivatives is disclosed in U.S. Pat. No. 4,423,209 and such compounds constitute important intermediates in the synthesis of other milbemycin derivatives which have valuable acaricidal, insecticidal and anthelmintic activities.
The process for preparing a 13-hydroxy-5-ketomilbemycin disclosed in this U.S. patent comprises treating a 13-hydroxy-5-methoxymilbemycin with mercuric acetate to give an enol ether, and then treating this enol ether with an acid. Such a process works efficiently and highly satisfactorily on a laboratory scale, but it has recently become apparent that certain disadvantages inherent in this process may make it difficult to carry out the process economically on the large scale required for industrial production. For example, the availability of the starting material for this process is limited, the reaction conditions required (notably the temperature) are inconvenient and the yields tend to be a little low. Moreover, since a highly poisonous mercuric compound is employed in the process, care needs to be taken to avoid pollution of the environment and poisioning of factory workers. These practical problems all add to the cost of industrial scale production and, exacerbated by the low yields, suggest that the prior art process may not be satisfactory for the large scale production of 13-hydroxy-5-ketomilbemycins.
We have now discovered a process for preparing these compounds which overcomes many of the disadvantages of the prior art process and which notably enables the products to be produced in significantly higher yields: on a laboratory scale, yields in the region of 50% have generally been achieved. It is believed that these factors will enable the process of the invention to be carried out more economically on an industrial scale than can the prior art process. In the course of developing the process of the invention, a certain new class of milbemycin derivatives has been discovered.